Diabetic retinopathy is a common complication of diabetes mellitus and a leading cause of severe vision loss and blindness around the world. The current interventions for DR, laser photocoagulation and vitrectomy, impede visual loss but do not improve vision for most patients at sight-threatening stages of DR. Both treatments are invasive surgery and have common side effects. There is no satisfactory pharmacotherapy for DR. Although the exact mechanisms of diabetic retinopathy are not known, several mechanisms are implicated in the development of diabetic retinopathy. Oxidative stress is believed to be a central pathogenic factor of all mechanisms. Therefore, searching for and developing new antioxidants represent a promising strategy to prevent and treat diabetic retinopathy. Curcumin, a polyphenolic compound derived from dietary spice turmeric, has a wide range of pharmacologic effects, including anti-proliferative, antioxidant, anti-inflammatory and anti-angiogenic activities. However, due to its poor bioavailability, the clinical application of curcumin is limited. In order to improve its bioavailability, curcumin structural analogs, adjuvant, liposomal curcumin, curcumin nanoparticles, curcumin phospholipid complex development are development and investigation. To develop compounds with increased antioxidant activities, a series of novel antioxidants, which have structural similarities to curcumin, have recently designed, synthesized and screened. Among these compounds screened, in vitro assays have demonstrated that CLT010-01, CLT010-07 and CLT010-12 have more potent inhibitory effect on retinal capillary endothelial and cancer cells than antioxidants curcumin and aminoguanidine. These three novel antioxidants significantly decreased the generation of reactive oxygen species and reduced the expression of vascular endothelial growth factor which plays a key role in retinal inflammation and vascular leakage in diabetic retinopathy. These findings suggest that these novel antioxidants have therapeutic potential in the treatment of diabetic retinopathy. These novel compounds possess novel structures and are patentable. Three novel antioxidants may be promising drug candidates for the treatment and prevention of diabetic retinopathy. The long-term goal of this project is to develop a new pharmacotherapy for diabetic retinopathy. The studies of this Phase I project will serve as a proof-of-concept study to determine the effect of these novel antioxidants in diabetic animals. This Phase I project will evaluate the efficacies of these novel antioxidants on oxidative stress, inflammation and retinal vascular permeability in a diabetic animal model and lay a solid ground for further studies in Phase II toward developing these antioxidant drugs. PUBLIC HEALTH RELEVANCE: Diabetic retinopathy is a common complication of diabetes mellitus and a leading cause of severe vision loss and blindness around the world. Currently, there is no satisfactory pharmacotherapy for diabetic retinopathy. Oxidative stress plays a critical role in the development of diabetic retinopathy. The long-term goal of this project is to develop novel, more effective, less toxic antioxidants for the prevention and treatment of diabetic retinopathy. We have demonstrated that three novel antioxidants CLT010-01, CLT010-07 and CLT010-12 have anti-proliferative, antioxidant and anti-inflammatory properties. The studies in this Phase I project will evaluate the efficacies of these antioxidants on oxidative stress, inflammation and retinal vascular permeability in an animal diabetic model and lay a solid ground for further studies in Phase II. These studies will contribute to the development of new treatment for diabetic retinopathy.